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Unité des Maladies Métaboliques et Micronutriments, INRA de Clermont-Ferrand/Theix, 63122 Saint Genès Champanelle, France
2 To whom correspondence should be addressed. E-mail: scalbert{at}clermont.inra.fr.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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KEY WORDS: • chlorogenic acid • absorption • gastrointestinal tract • stomach • rats
Chlorogenic acid, an ester of caffeic acid, is found with quinic acid in a wide range of fruits and vegetables and is particularly abundant in coffee (1). Both chlorogenic and caffeic acid possess antioxidant properties in vivo (2–4). Chlorogenic acid and caffeic acid were reported to prevent different cancers and cardiovascular diseases in several experimental studies in animal models (5–9). The biological properties of hydroxycinnamic acids depend on their absorption in the gut and on their metabolism. The intestinal absorption of caffeic acid is well characterized in both experimental animals and human subjects (10–13). The absorption and metabolism of chlorogenic acid are less studied. Caffeic acid appeared rapidly in plasma after chlorogenic acid ingestion in both rats and human subjects, suggesting that chlorogenic acid is hydrolyzed in the upper part of the gastrointestinal tract (13,14). Using an in situ intestinal perfusion model, we could confirm that chlorogenic acid was effectively absorbed in the small intestine of rats, hydrolyzed in the mucosa, and recovered as free phenolic acid in the plasma (15). However, other authors also identified intact chlorogenic acid in human urine after ingestion of chlorogenic acid, chlorogenic acid-containing coffee, or prune, with recovery yields varying from 0.3 to 2.3%, suggesting that chlorogenic acid is also absorbed without hydrolysis (12,16–18). More recently, chlorogenic acid was also identified in rabbit plasma shortly after oral administration of a honeysuckle extract (19).
The aim of this work was to explore the stability of chlorogenic acid in the gut, the form under which it is absorbed through the gut mucosa and the site of absorption along the gastrointestinal tract. Rats were fed a diet supplemented with chlorogenic acid, and phenolic acids were estimated in the stomach, small intestine, and cecal contents at different time points during the meal as well as in bladder urine and plasma. Absorption of chlorogenic acid through the stomach mucosa was also examined by infusing chlorogenic acid into the stomach of food-deprived rats.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Animals and diets.
Male Wistar rats, weighing 
180 g, were caged singly in temperature-controlled rooms (22°C), with a dark period from 0800 to 2000 and with access to food from 0800 to 1600. They were fed a semipurified control diet for 7 d (Table 1). Rats were maintained and handled according to the recommendations of the National Institute for Agricultural Research Ethics Committee, in accordance with Decree 87-848. For 3 d, 16 rats were then fed the same diet supplemented with chlorogenic acid (0.25% wt/wt) (Table 1). These quantities of chlorogenic acid in the diet correspond to a consumption of 7 cups of coffee/d for humans [for a diet consumption of 500 g dry matter/d, an amount of chlorogenic acid in coffee of 750 mg/100 L and a cup volume of 200 mL (1)]. Diet intake was measured on the last day when each rat was killed and chlorogenic acid consumption was calculated accordingly. Six other rats were deprived of food for 24 h before the stomach infusion experiment.
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For gastric infusion, rats (n = 4) were anaesthetized with sodium pentobarbital (40 mg/kg body weight) and kept alive under anesthesia throughout the experiment. After cannulation of the biliary duct, the pylorus was ligated and the stomach was filled in situ through the cardia with a 5-mL chlorogenic acid solution buffered to mimic the osmotic and pH conditions found in the stomach during a meal. This buffer (pH 3) maintained at 37°C, contained KH2 PO4 (7.5 mmol/L), NaCl (50 mmol/L), KCl (50 mmol/L), CaCl2 (2 mmol/L), acetic acid (25 mmol/L), lactic acid (25 mmol/L), MgSO4 (1 mmol/L), polyethylene glycol (PEG)3 6000 (5 g/L), and chlorogenic acid (7 mmol/L). Chlorogenic acid was stable in buffer under the experimental conditions (data not shown). Thus, the stomach contained 35 µmol of chlorogenic acid. The cardia sphincter was ligated to prevent any gastroesophageal reflux. The amount of chlorogenic acid infused into the stomach was established to fit in the quantities found in the stomach during the chlorogenic acid feeding experiment. The stomach contents were collected 30 min later; blood was withdrawn from the gastric vein and abdominal aorta into heparinized tubes and centrifuged (10,000 x g; 2 min). Two more rats were used as control, infused with the same buffer without chlorogenic acid, and their blood treated under identical conditions. Plasma samples were acidified with 10 mmol/L acetic acid. All samples were stored at –20°C before analysis.
Treatment of gut content samples. The contents of the stomach, small intestine, and cecum collected from rats fed the chlorogenic acid–supplemented diet were spiked with sinapic acid as an internal standard. Then 9 volumes of methanol:H2O:concentrated HCl (70:28:2, by vol) containing sinapic acid was added to 1 volume of each content, mixed on a vortex for 30 s, sonicated at 0°C, and centrifuged for 10 min at 4°C and 3000 x g. The supernatant was diluted with water (1:1, v:v), 1 mL of hexane was added, and vortex mixing took place. After centrifugation (3000 x g; 10 min), the upper organic phase was removed and the lower one was diluted 25 times in methanol:H2O:concentrated HCl (70:28:2, by vol) except for cecal samples, which were analyzed directly.
For the gastric infusion experiment, the stomach contents were centrifuged (3000 x g; 10 min), filtered on fritted glass, and analyzed directly. Phenolic acid concentrations in the stomach lumen were corrected for variations in volume due to gastric secretion. PEG, a compound not absorbed in the stomach, was added to the gastric buffer, and its concentration in the gastric buffer determined at the beginning and at the end of the experiment (20). The ratio between these 2 concentrations reflected the intensity of the gastric secretion.
Treatment of plasma and urine samples. Before analysis, urine samples were diluted with 0.5 mol/L sodium acetate containing 2 g/L ascorbic acid to reach pH 6.8. Plasma samples were adjusted to pH 6.8 with 0.1 volume of 0.5 mol/L sodium acetate containing 2 g/L ascorbic acid. Urine and plasma samples were incubated for 4 h at 37°C in the presence of 10 µL ß-glucuronidase (2 x 108 U/L) from Escherichia coli. This enzyme was selected rather than the Helix pomatia enzyme preparation because we noticed that chlorogenic acid was partially hydrolyzed by this last enzyme mixture (18) but was stable when treated in this enzyme preparation of esterase activity able to hydrolyze chlorogenic acid. The presence of sulfatase activity in the E. coli enzyme preparation was verified using a rat plasma sample containing known sulfate esters of quercetin (data not shown). Phenolic acids in treated samples were extracted by adding 2.85 volumes of methanol:H2O:con-centrated HCl (70:28:2, by vol) and centrifuged for 4 min at 12,000 x g. The resulting supernatant was analyzed by HPLC as described below.
Phenolic acid analyses. Phenolic acids in gut contents and plasma and urine were analyzed by HPLC coupled to an 8-electrode CoulArray Model 5600 detector (Eurosep) with potentials set at 25, 100, 250, 325, 360, 400, 475, and 550 mV. The system was fitted with a 5µm-C-18 Hypersil BDS analytic column (150 x 4.6 mm; Life Sciences International). Mobile phase A was 5% acetonitrile in 30 mmol/L NaH2PO4 at pH 3, and mobile phase B, 50% acetonitrile in 30 mmol/L NaH2PO4 at pH 3. The separation was performed at 35°C. The flow rate was 0.8 mL/min. Two different gradients were applied for content analysis and fluid analysis. For content analysis, the gradient was as follows: linear from 0 to 60% B from 0 to 45 min; linear from 60 to 100% B from 45 to 46 min; 100% B from 46 to 50 min. For plasma and urines analyses, the gradient was as follows: linear from 0 to 22% B from 0 to 21 min; linear from 22 to 29% B from 21 to 41 min; 100% B from 41 to 45 min. In plasma, recoveries ranged from 75–85% according to the nature of the phenolic acids. The precision and accuracy for each of the standard curve detection concentration points after back-calculation were 1.93–3.89% and –0.11–2.07%, respectively. The limits of detection were 0.06 µmol/L for caffeic and ferulic acids, and 0.08µmol/L for chlorogenic and isoferulic acids.
Plasma samples, collected in the gastric vein and abdominal aorta after the gastric infusion experiment, were analyzed by HPLC-electrospray ionization-tandem mass spectrometry (HPLC-ESI-MS/MS; API 2000, Applied Biosystem, Canada). Plasma was treated as above and injected directly (40 µL) into the LC-ESI-MS-MS system, fitted with a YMC-Pack ODS-AM column (250 x 3.0 mm I.D, 5-µm particle size, YMC Europe) and a YMC-Pack ODS-AM guard column (10 x 4 mm I.D, 5-µm particle size, YMC Europe). The mobile phase consisted of water:acetonitrile:formic acid (94.5:4.5:1, by vol) (solvent A) and water:acetonitrile:formic acid (49.5:49.5:1, by vol) (solvent B). The eluent was delivered at a 200 µL/min flow rate as follows: 5% solvent B from 0 to 10 min, 5–10% solvent B from 10 to 12 min, 10–27% solvent B from 12 to 14 min, 27–29% solvent B from 14 to 19 min, and 29% solvent B up to 30 min. The ionization conditions were adjusted at 400°C and –5000 V for drying gas temperature and voltage, respectively. The other ionization parameters were as follows: nebulizer gas (N2) 70 arbitrary units (au), drying gas (N2) 30 au, and curtain gas (N2) 20 au. The common nitrogen flow for collision active dissociation was set at 1.2 au. The particular MS voltages and collision energies for chlorogenic, caffeic, ferulic, and isoferulic acids were optimized (data not shown). The analyses were performed in the negative and multiple reaction monitoring (MRM) modes. The selected MS transitions were 353/191, 179/135, and 193/134 for chlorogenic, caffeic and ferulic/isoferulic acids, respectively. The phenolic acids were identified by comparison of the signals and retention times to those of corresponding standards. Conjugations of chlorogenic, caffeic, ferulic/isoferulic acids, and p-coumaric acid with glucuronic acid (m/z, 529/353, 355/179, 369/193, respectively), sulfate groups (m/z, 433/353, 259/179, 273/193, respectively), glycine (m/z, 410/353, 236/179, 250/193, respectively), glutathione (m/z, 642/353, 468/179, 482/193, respectively) and with both glucuronide and sulfate groups (m/z, 609/353, 435/179, 449/193, respectively) were also investigated in the MRM mode using the same MS voltages as applied to the corresponding free phenolic acids. MS transitions were determined from the analysis of appropriate standards (sulfate ester of ferulic acid and p-coumaric acid, glucuronide of ferulic and p-coumaric acid) or calculated (loss of conjugated group) when the standard was missing.
Data analysis. Numerical values are means ± SEM (n = 4 for bioavailability study or 6 for gastric infusion study). Data were analyzed using XLStat version 7.5 Addinsoft 2004. Significant differences were determined by 1-way ANOVA (gastric infusion experiment) or by 2-way ANOVA. Data were log-transformed when non-Gaussian distribution occurred. When significant differences were detected Tukey's Multiple Comparison Test was used to assess differences among the means. Differences with P < 0.05 were considered significant.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Diet consumption and chlorogenic acid intake. Chlorogenic acid was administered with the diet (0.25%) from the beginning of the dark period and its consumption was determined for the next 7 h. The total amounts of chlorogenic acid consumed were as follows: 145.4 ± 16.7 µmol from 0 to 1.5 h, 37.3 ± 7.4 µmol from 1.5 to 3 h, 25.6 ± 5.6 µmol from 3 to 4.5 h, and 31.4 ± 7.5 µmol from 4.5 to 7 h.
The major part of the meal and of chlorogenic acid (60.5%) was ingested during the first 90 min of this period. Rats ingested lower amounts of chlorogenic acid during the next 3 periods (15.6, 10.7 and 13.1%, respectively). The amount of chlorogenic acid ingested during the first 90 min was greater than during the other periods (P < 0.001).
Chlorogenic and caffeic acid concentrations in gastrointestinal contents. In the stomach, similar quantities of chlorogenic acid were found at the end of each time period. In the small intestine, the chlorogenic acid content increased significantly after 3 h. The contents at 4.5 and 7 h did not differ from that at 3 h (Fig. 1). Only traces of caffeic acid (1.0 ± 0.1% of total phenolic acids) could be detected in either the stomach or the small intestine.
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Plasma kinetics of chlorogenic acid and its metabolites. No chlorogenic acid or other phenolic acids were detected in the aortic plasma of the control group. In the supplemented group, both chlorogenic and caffeic acids were detected in similar concentrations early (1.5 h) after the beginning of the meal (Table 2). The concentrations did not differ during the meal. No ferulic or isoferulic acid could be detected.
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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20% of chlorogenic acid is hydrolyzed by the microflora in this low part of the gut. This result is consistent with in vitro experiments in which chlorogenic acid was partially hydrolyzed by human fecal bacteria (22,23). Chlorogenic acid appeared early in both plasma and urine, 1.5 h after the beginning of the meal. A similar fast absorption was also reported in rabbits with a maximal absorption peak of chlorogenic acid observed 35 min after administration (19). This rapid appearance of the intact ester in plasma or urine suggests a direct absorption in the stomach or in the small intestine. The latter is unlikely as suggested by our previous intestinal perfusion experiments with chlorogenic acid, in which no chlorogenic acid but only free phenolic acids could be detected in the mesenteric vein (15). We therefore explored chlorogenic acid absorption in the ligated stomach of rats. Chlorogenic acid was absorbed in the stomach and was identified in both the gastric vein and aorta in its intact form. Using a similar model, several polyphenols such as daidzein, genistein, quercetin, rutin, anthocyanins or ferulic acid were shown to be absorbed in the stomach (24–29). The direct absorption of chlorogenic acid shows that esterification with quinic acid does not prevent its absorption in the stomach. In contrast to our previous experiments with perfused small intestine, the absence of caffeic acid or of its conjugated forms in the gastric vein and aorta shows that the absorption of chlorogenic acid in the stomach follows different mechanisms. Chlorogenic acid could be absorbed through the bilitranslocase, which is involved in the transport of anthocyanins in the stomach (28,30) or through other unidentified organic anion transporters. Passive transport of chlorogenic acid was also described in Caco-2 cell cultures (31).
Caffeic acid also appears early in plasma and urine (Table 2, Figure 3). Its O-methylated derivatives, ferulic and isoferulic acids, were also present in urine. They most likely arose from the absorption and hydrolysis of chlorogenic acid in the mucosa of the small intestine as suggested previously (15,26). Other authors reported that caffeic acid was detected early in plasma, 30 to 60 min after consumption of pure chlorogenic acid or coffee by rats or humans (13,14). These authors suggested that chlorogenic acid was hydrolyzed in the upper digestive tract because they could not detect any chlorogenic acid in plasma. The absence of chlorogenic acid would most likely be explained by a too rapid transit through the empty stomach in these 2 studies carried out with chlorogenic acid solutions or brewed coffee in food-deprived rats or fasting humans. In contrast, when volunteers consumed coffee with a whole breakfast, chlorogenic acid was present in urine (18).
The fraction of chlorogenic acid that is not absorbed in the upper intestinal tract reaches the cecum. The low amounts of chlorogenic acid estimated in the cecal content suggest an intense microbial metabolism. Chlorogenic acid is hydrolyzed into caffeic acid and further degraded to low-molecular-weight phenolic acids such as m-coumaric acid, 3-hydroxyphenylpropionic acid, or 3-hydroxybenzoic acid (32,33). These metabolites were shown to be the main metabolites identified in rat urine, together with much lower amounts of intact caffeic acid and its O-methylated metabolites (33).
In conclusion, this study shows for the first time that chlorogenic acid is not hydrolyzed in the stomach and the small intestine, but absorbed in the stomach in its intact form and as hydrolyzed forms such as caffeic and (iso)ferulic acids in the small intestine. Once reaching the cecum, chlorogenic acid is hydrolyzed into caffeic acid and further metabolized into other aromatic acids. Further studies will be required to understand the exact mechanisms of absorption and identify the transporters involved in the different parts of the gastrointestinal tract. Moreover, the role of the stomach in polyphenol absorption and the influence of the food matrix on absorption should be investigated further.
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: ESI, electrospray ionization; MRM, multiple reaction monitoring; PEG, polyethylene glycol.
Manuscript received 23 November 2005. Initial review completed 14 December 2005. Revision accepted 3 February 2006.
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